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Science. 2018 Oct 5;362(6410):86-91. doi: 10.1126/science.aau1549. Epub 2018 Aug 30.

Gene editing restores dystrophin expression in a canine model of Duchenne muscular dystrophy.

Author information

1
Department of Molecular Biology, Hamon Center for Regenerative Science and Medicine, Sen. Paul D. Wellstone Muscular Dystrophy Cooperative Research Center, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA.
2
Exonics Therapeutics, 75 Kneeland Street, Boston, MA 02111, USA.
3
Department of Clinical Science and Services, Comparative Neuromuscular Diseases Laboratory, Royal Veterinary College, London NW1 0TU, UK.
4
Section of Anaesthesia and Analgesia, Royal Veterinary College, London NW1 0TU, UK.
5
Department of Internal Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA.
6
Department of Molecular Biology, Hamon Center for Regenerative Science and Medicine, Sen. Paul D. Wellstone Muscular Dystrophy Cooperative Research Center, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA. eric.olson@utsouthwestern.edu.

Abstract

Mutations in the gene encoding dystrophin, a protein that maintains muscle integrity and function, cause Duchenne muscular dystrophy (DMD). The deltaE50-MD dog model of DMD harbors a mutation corresponding to a mutational "hotspot" in the human DMD gene. We used adeno-associated viruses to deliver CRISPR gene editing components to four dogs and examined dystrophin protein expression 6 weeks after intramuscular delivery (n = 2) or 8 weeks after systemic delivery (n = 2). After systemic delivery in skeletal muscle, dystrophin was restored to levels ranging from 3 to 90% of normal, depending on muscle type. In cardiac muscle, dystrophin levels in the dog receiving the highest dose reached 92% of normal. The treated dogs also showed improved muscle histology. These large-animal data support the concept that, with further development, gene editing approaches may prove clinically useful for the treatment of DMD.

PMID:
30166439
PMCID:
PMC6205228
DOI:
10.1126/science.aau1549
[Indexed for MEDLINE]
Free PMC Article

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